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Cerebral vascular calcium signaling in diabetic Alzheimer's disease-related dementias

糖尿病阿尔茨海默病相关痴呆的脑血管钙信号传导

基本信息

批准号：
10117843
负责人：
YONG-XIAO WANG
金额：
$ 32.6万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2024-08-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117843
关键词：
Address Agreement Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Animals Award Biology Blood Blood Vessels Blood flow Calcium Signaling Cell Hypoxia Cells Cerebrovascular Circulation Cerebrum Cessation of life Cognitive Complex Data Dementia Deterioration Development Diabetes Mellitus Diabetic mouse Disease Dissociation Funding Funding Opportunities Hypoxia Impaired cognition In Vitro Knock-out Lead Link Mediating Mediation Memory Memory Loss Memory impairment Mitochondria Molecular Mus Nerve Degeneration Organ Oxidative Stress Pathologic Pathway interactions Pilot Projects Process Production Reactive Oxygen Species Research Research Personnel Rieske iron-sulfur protein Risk Factors Role Ryanodine Receptor Calcium Release Channel Series Site Smooth Muscle Smooth Muscle Myocytes Tacrolimus Binding Proteins Testing United States National Institutes of Health Vascular Dementia Vascular Smooth Muscle Wild Type Mouse Work antioxidant therapy base cerebral artery cerebral hypoperfusion cerebrovascular comorbidity diabetic experimental study glucose metabolism improved in vivo innovation knockout gene new therapeutic target novel overexpression programs protein expression response therapeutic target therapeutically effective vascular cognitive impairment and dementia vasoconstriction

项目摘要

Alzheimer's disease (AD) and AD-related dementias (ADRD) are the common incurable neurodegenerative even conditions characterized by progressive cognitive deterioration, memory decline and death. The major forms of ADRD include vascular contributions to cognitive impairment and dementia (VCID). In agreement, vascular dementia is the second most common form of dementia and the most frequent comorbidity with AD. Diabetes may production is a leading factor in the development of VCID; the ole of diabetes primarily occur due to the abnormal glucose metabolism and i ncreased reactive oxygen species (ROS) in cerebral vascular smooth muscle cells (CASMCs) r . In support, antioxidant therapies have shown promising results in protecting against diabetes-induced VCID and other dementias. the molecular mechanisms that link diabetes to the development of VCID remain to be elucidated, and current treatments for these diseases are neither always effective nor specific. The Based on our preliminary findings with previous work, in this project, we propose a novel central hypothesis that diabetes increases Rieske iron-sulfur protein (RISP)-mediated mitochondrial ROS, dissociates FK506 binding protein 12.6 (FKBP12.6) from type-2 ryanodine receptor (RyR2) to remove its inhibitory effect on RyR2 channel and induce Ca2+ release, which causes cerebral vasoconstriction and cerebral blood flow reduction, thereby leading to progressive memory loss, cognitive decline and VCID. To test this exciting hypothesis, we will conduct a series of mechanistic studies primarily by employing smooth muscle-specific RISP, RyR2, and FKBP12.6 knockout (KO) and/or overexpression (OE) mice with other complementary advanced experimental approaches to address the following specific questions (Specific Aims): Aim 1: Are the increased RISP-mediated mitochondrial ROS in CASMCs essential for VCID induced by diabetes? Aim 2: Is RyR2/FKBP12.6 complex dissociation a key consequence for the increased RISP-mediated mitochondrial ROS to mediate VCID induced by diabetes? The objectives of the present proposal are not only to enhance our understanding of the molecular mechanisms for VCID, ADRD devastating diseases. and AD, but also help to identify novel therapeutic targets for these common

阿尔茨海默病（AD）和AD相关性痴呆（ADRD）是常见的不治之症，神经变性甚至以进行性认知退化、记忆衰退和死亡ADRD的主要形式包括血管对认知障碍和痴呆的贡献（VCID）。血管性痴呆是痴呆症的第二大常见形式，常与AD合并。糖尿病可以生产是VCID发展的主导因素;糖尿病的OLE 主要是由于葡萄糖代谢异常和活性氧（ROS）增加而发生的脑血管平滑肌细胞（CASMC） R .作为支持，抗氧化剂疗法在预防糖尿病引起的VCID和其他痴呆症方面显示出有希望的结果。的将糖尿病与VCID发展联系起来的分子机制仍有待阐明，目前对这些疾病的治疗既不总是有效也不总是特异性的。的基于我们的初步研究结果与以前的工作，在这个项目中，我们提出了一个新的中央假设糖尿病增加了Rieske铁硫蛋白（RISP）介导的线粒体ROS，将FK 506结合蛋白12.6（FKBP12.6）与2型兰尼碱受体（RyR 2）解离以去除其抑制RyR 2通道并诱导Ca 2+释放，导致脑血管收缩，脑血流量减少，从而导致进行性记忆丧失、认知能力下降和VCID。为了验证这一令人兴奋的假设，我们将进行一系列的机制研究，主要是通过使用平滑肌特异性RISP、RyR 2和FKBP12.6敲除（KO）和/或过表达（OE）小鼠，解决以下具体问题的其他补充性先进实验方法（具体目标）：目的1：在CASMCs中增加的RISP介导的线粒体ROS对于VCID是必需的吗？糖尿病？目的2：RyR 2/FKBP12.6复合物解离是否是RISP介导的细胞凋亡增加的关键结果？线粒体ROS介导糖尿病诱导的VCID？本提案的目的不仅是为了加强我们对分子生物学的理解， VCID、ADRD机制毁灭性的疾病和 AD，还有助于确定这些常见疾病的新治疗靶点，